Age is the major risk factor for cardiovascular diseases (CVD). Two key contributors to the increased risk of CVD in middle-aged and older (MA/O) adults are stiffening of the large elastic arteries and the development of vascular endothelial dysfunction, indicated by impaired nitric oxide (NO)-induced endothelium-dependent dilation (EDD). The mechanisms by which aging causes arterial dysfunction are incompletely understood, but involve reductions in NO bioavailability associated with the development of oxidative stress. Thus, establishing novel strategies to reduce arterial stiffness and increase vascular endothelial function in MA/O adults by increasing NO bioavailability and reducing oxidative stress is a high biomedical research priority. Curcumin is a naturally occurring polyphenol found in the Indian spice turmeric that improves physiological function in animal models of age-related diseases and is a promising nutraceutical for intervention in the aging process. Our preclinical results indicate that chow supplemented with curcumin reduces aortic pulse wave velocity (PWV), the most common and clinically important measure of large elastic artery stiffness, restores NO-mediated EDD and reduces arterial oxidative stress in old C57/BL6 mice. The goal of the present R21 application is to translate these preclinical observations to humans. We propose a pilot study using well-established procedures to determine the efficacy of oral curcumin supplementation for reducing large elastic artery stiffness and improving vascular endothelial function in MA/O adults. Hypothesis 1: Oral curcumin therapy will reduce large elastic artery stiffness and increase NO-mediated EDD in MA/O adults without clinical disease, and the improvements will be greater with a higher vs. lower dose. Hypothesis 2: The improvements in vascular function will be associated with evidence consistent with reduced oxidative stress and inflammation, and, perhaps, selective changes in platelet function and prostanoid metabolism. Impact on the Field. The biomedical significance of the proposed work includes: 1. Determining the efficacy of oral curcumin therapy for reducing large elastic artery stiffness and reversing vascular endothelial dysfunction in MA/O adults without clinical disease; 2. Determining if the benefits of supplementation are greater with a higher vs. lower dose of curcumin; 3. Providing initial insight into the mechanisms by which these treatment benefits may be conferred; 4. Establishing evidence for performing a larger, more comprehensive randomized clinical trial that will: extend testing of the efficacy of curcumin therapy to MA/O adults with major risk factors for developing CVD (e.g., hypertension, hyperlipidemia, metabolic syndrome) and/or patients with clinical CVD; determine the effects of oral curcumin therapy on local carotid artery compliance and intima-media thickness, and provide insight into the mechanisms of action.